Method for obtaining a purified hydrofluoroalkane, purified hydrofluoroalkane, use of same and method for analysing same

ABSTRACT

Process for the production of a hydrofluoroalkane, according to which hydrofluoroalkane comprising organic impurities is subjected to at least two distillations.

REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/EP01/02806 filed Mar. 7, 2001.

A subject-matter of the present invention is a process for theproduction of a purified hydrofluoroalkane, a purifiedhydrofluoroalkane, the use of the hydrofluoroalkane and a method for theanalysis of a hydrofluoroalkane.

Some hydrofluoroalkanes, such as in particular 1,1,1,2-tetrafluoroethaneand 1,1,1,2,3,3,3-heptafluoropropane, can be used, because of theirphysical properties and of their favourable toxicology, inpharmaceutical applications, in particular as propellent gas in medicalaerosols.

The industrial production of such hydrofluoroalkanes provides, however,a product which comprises saturated and unsaturated impurities. As theseimpurities are often toxic, strict standards are likely to be adopted,limiting the content, for example, of olefinic impurities to less than 5ppm by volume (see, for example, the draft standard of the FDA (Food andDrug Administration, Center for Drug and Evaluation and Research,October 1998) relating to the content of the said impurities in1,1,1,2-tetrafluoroethane for MDI products).

Consequently, it is necessary to purify the hydrofluoroalkane ofindustrial grade in order to obtain a product of pharmaceutical grade.It is also necessary to have available analytical methods which make itpossible to detect and to identify traces of unsaturated and saturatedorganic impurities in the hydroflubroalkane. This presents problems, inparticular when these impurities have a boiling point close to that ofthe hydrofluoroalkane.

Patent Application WO-A-90/8750 relates to a process for thepurification of 1,1,1,2-tetrafluoroethane from olefinic impurities,according to which the 1,1,1,2-tetrafluoroethane is subjected tocatalytic hydrogenation. According to this known process, contentsranging up to 10 ppm of a single olefinic impurity, namely1,1-difluoro-2-chloroethylene, are observed. According to the patentapplication, the detection limit for 1,1-difluoro-2-chloroethylene is 10ppm. Furthermore, this known process does not make possible satisfactorypurification from all the saturated and unsaturated organic impurities.In particular, this known process does not make, it possible to remove1,1,2,2-tetrafluoroethane (HFC-134). The presence of substantial amountsof HFC-134 in 1,1,1,2-tetrafluoroethane for pharmaceutical applicationsis not desirable since its toxicity has not been examined to any extent.

It was consequently desirable to have available an efficientmanufacturing process which makes possible access to a purifiedhydrofluoroalkane, preferably of pharmaceutical grade. It wasparticularly desirable to have available a manufacturing process whichmakes possible an efficient reduction in the content of each individualorganic impurity while achieving very low overall contents of organicimpurities.

The invention consequently relates to a process for the production of apurified hydrofluoroalkane, according to which the hydrofluoroalkane,comprising organic impurities, is subjected to at least twodistillations, the second distillation being carried out at a pressuregreater than that of the first distillation, and at least one fractioncomposed of hydrofluoroalkane purified from organic impurities isrecovered at the outlet of the second distillation. Generally, thisfraction can be used directly for pharmaceutical applications. However,the process according to the invention does not rule out one or moreadditional finishing stages.

The process according to the invention is particularly well suited tothe production of a purified hydrofluoroalkane which can be used forpharmaceutical applications.

In a first alternative form of the process according to the invention,the heavy impurities are separated from the hydrofluoroalkane in thefirst distillation and the light impurities are separated from thehydrofluoroalkane in the second distillation.

In a second alternative form of the process according to the invention,which alternative form is preferred, the light impurities are separatedfrom the hydrofluoroalkane in the first distillation and the heavyimpurities are separated from the hydrofluoroalkane in the seconddistillation. In this case, the fraction composed of hydrofluoroalkanepurified from organic impurities is recovered at the top of the seconddistillation.

The term “light impurity” is understood to denote an impurityexhibiting, at the pressure of the distillation, a boiling point lowerthan that of the hydrofluoroalkane. The term “heavy impurity” isunderstood to denote an impurity exhibiting, at the pressure of thedistillation, a boiling point greater than that of thehydrofluoroalkane.

It has been found, surprisingly, that the process according to theinvention makes possible an extremely efficient purification ofhydrofluoroalkane from saturated and unsaturated organic impurities,thus providing hydrofluoroalkane exhibiting a low content of the saidorganic impurities, in particular as regards its content of saturatedimpurities and, if appropriate, of (chloro)fluoroethenes and(chloro)fluoropropenes.

The process according to the invention applies to any hydrofluoroalkane.It applies in particular to the hydrofluoroalkanes capable of being usedin pharmaceutical applications. Mention may be made, for example, ofhydrofluoroethanes, hydrofluoropropanes and hydrofluorobutanespreferably exhibiting a low toxicity towards man. Specific examples ofsuch hydrofluoroalkanes are 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3-pentafluoropropane and1,1,1,3,3-pentafluorobutane. Among these hydrofluoroalkanes, the processaccording to the invention applies preferably to1,1,1,2-tetrafluoroethane and to 1,1,1,2,3,3,3-heptafluoropropane. Theprocess according to the invention applies in a very particularlypreferred way to the production of 1,1,1,2-tetrafluoroethane ofpharmaceutical grade.

The pressure in the first distillation is generally less than 10 barabsolute. It is often at most 9 bar. It is preferably at most 8 bar. Thepressure in the first distillation is generally at least 1 bar. It isoften at least 1.5 bar. It is preferably at least 2 bar.

The pressure in the second distillation is generally greater than 10 barabsolute. It is often at least 12 bar. It is preferably at least 15 bar.In a particularly preferred way, it is at least 17 bar. In a veryparticularly preferred way, it is at least 19 bar. The pressure in thesecond distillation is generally at most 40 bar. It is often at most 30bar. It is preferably at most 25 bar.

In the present description, any reference to the pressure corresponds tothe absolute pressure measured at the top of the distillation column.

The temperature at which the first or the second distillation is carriedout corresponds approximately to the boiling point of thehydrofluoroalkane at the pressure chosen for the respectivedistillation.

Each of the two distillations can be carried out in one or moredistillation columns. Use will preferably be made of a single column perdistillation.

The distillation columns which can be used in the process according tothe invention are known per se. Use may be made, for example, ofconventional plate columns or plate columns of dual-flow type oralternatively of columns with bulk or structured packing.

The number of theoretical plates in the first distillation is generallyat least 10. It is often at least 15. A number of at least 20 gives goodresults.

The number of theoretical plates in the second distillation is generallyat least 20. It is often at least 30. A number of at least 40 gives goodresults.

The molar reflux ratio in the first distillation is generally at least50.

The molar reflux ratio in the second distillation is generally at least5.

It has been found that the process according to the invention makespossible an extremely efficient purification of the hydrofluoroalkanefrom saturated and unsaturated organic impurities, thus providinghydrofluoroalkane exhibiting a low content of the said organicimpurities, in particular as regards, if appropriate, its content of(chloro)fluoroethenes, of (chloro)fluoropropenes and of saturatedimpurities. This is because the process according to the invention makespossible the production of a hydrofluoroalkane in which the content ofeach individual organic impurity has been greatly reduced.

The invention consequently also relates to a hydrofluoroalkaneexhibiting an individual content of each organic impurity of less than10 molar ppm. This individual content is preferably at most 8 ppm. In aparticularly preferred way, this individual content is at most 5 ppm. Anindividual content of at most 2.8 ppm is very particularly preferred. Anindividual content of at most 1 ppm is even more preferred.

The contents of impurities in the hydrofluoroalkane according to theinvention can advantageously be determined according to the methoddescribed in Example 4. The hydrofluoroalkane according to the inventioncan preferably be used for pharmaceutical applications.

The total content of organic impurities in the hydrofluoroalkaneaccording to the invention is generally at most 200 molar ppm. Thistotal content is often at most 100 ppm. The total content is more oftenat most 50 ppm. The total content is preferably at most 30 ppm. In aparticularly preferred way, the total content is at most 25 ppm. A totalcontent of at most 20 ppm is even more preferred. The total content caneven be at most 5 ppm.

The total content of unsaturated organic impurities in thehydrofluoroalkane according to the invention is generally at most 5molar ppm. This content is often at most 3 ppm. The content is moreoften at most 2 ppm. The content is preferably at most 1.8 ppm. In aparticularly preferred way, the content is at most 1.7 ppm.

Hydrofluoroalkane is preferably 1,1,1,2-tetrafluoroethane.

The content of fluoropropenes determined in the1,1,1,2-tetrafluoroethane according to the invention is generally lessthan 1.4 molar ppm. This content is often at most 1.2 ppm. The contentis more often at most 1.0 ppm. The content is preferably at most 0.9ppm. In a particularly preferred way, the content is at most 0.8 ppm.

The content of 1,1,2,2-tetrafluoroethane in the1,1,1,2-tetrafluoroethane according to the invention is generally lessthan 10 molar ppm. The content is preferably at most 8 ppm. In aparticularly preferred way, the content is at most 5 ppm. In an evenmore preferred way, the content is at most 2 ppm.

The invention also relates to a method for the analysis of the contentof organic impurities in a hydrofluoroalkane, in which method

-   (a) the hydrofluoroalkane is subjected to a chromatography operation    and;-   (b) an operation is carried out in which the organic impurities are    detected by mass spectrometry.

The method according to the invention makes it possible, surprisingly,to determine, in a single analytical operation, the nature and theamount of a large number of organic impurities present in ahydrofluoroalkane. The method according to the invention even makes itpossible to carry out a quantitative detection of several organicimpurities exhibiting between them the same retention time in thechromatography operation. In a particularly surprising way, the methodaccording to the invention also makes possible the quantitativedetection of impurities which exhibit the same retention time in thechromatography operation as the hydrofluoroalkane.

It has also been found thatHCFC-124(1,1,1,2-tetrafluoro-2-chloroethane), which is an impurity whichmay be present in 1,1,1,2,3,3,3-heptafluoropropane and which could notbe determined simultaneously with other organic impurities prior to thepresent invention, can be analysed in the same operation with the otherorganic impurities by virtue of the method according to the invention.

The chromatography operation is preferably a gas chromatographyoperation.

The stationary phase in the chromatography operation is generallynonpolar. A polymer of polysiloxane type is often employed as stationaryphase. A stationary phase composed of optionally crosslinkedpolydimethylsiloxane has given good results. In the case of gaschromatography, good results have been obtained with an Rtx®-1 gaschromatography column sold by Restek Corp.

In an alternative form, the stationary phase exhibits moderate polarity.Such a stationary phase can be composed, for example, of a mixture ofnonpolar polymer as described above with a polar polymer. Such polarpolymers are chosen, for example, from polymers functionalized by polargroups, in particular from functionalized polyolefins orpolyalkylsiloxanes. The polar group can be chosen, for example, fromhydroxyl, ether, ester, phenoxy and, preferably, from nitrile. Apolysiloxane of general formula

in which R is a C₁ to C₄ alkyl group, preferably a methyl group, isparticularly preferred as polar polymer. In the alternative formdescribed above, the content of polar polymer is generally greater thanor equal to 1% by weight of the stationary phase. This content is oftengreater than or equal to 2% by weight. It is preferably greater than orequal to approximately 5% by weight. The content of polar polymer isgenerally less than or equal to 15% by weight of the stationary phase.The content is often less than or equal to 10% by weight. It ispreferably less than or equal to approximately 8% by weight.

The initial temperature of the chromatography operation is generallyadjusted at the most to 40° C. This temperature is often adjusted at themost to 0° C. This temperature is more often adjusted at the most to−20° C. This temperature is preferably adjusted at the most to −40° C.As a general rule, it is at least −80° C.

In the chromatography operation, there is generally at least one stagewith a constant temperature gradient which provides a controlledtemperature rise starting from the initial temperature. This temperaturegradient is generally at least 0.1° C./min. It is preferably at least0.5° C./min.

The temperature gradient is generally at most 10° C./min. It ispreferably at most 2° C./min.

The column is preferably a capillary column. The length of the column isgenerally at most 200 m. The length is often at most 120 m. The lengthof the column is generally at least 20 m.

The injection can be carried out in split or splitless mode. Injectionin split mode is preferred.

The carrier gas is often chosen from helium and hydrogen. Helium ispreferred.

The internal diameter of the column is generally at most 0.32 mm. Thediameter is often at most 0.25 mm. The diameter is preferably at most0.20 mm. The internal diameter of the column is often at least 0.10 mm.The diameter is preferably at least 0.15 mm.

The thickness of the stationary phase film deposited inside the columnis generally at least 0.5 μm. The thickness is preferably greater thanor equal to approximately 1 μm. The thickness of the stationary phasefilm deposited inside the column is generally at most 5 μm.

A specific alternative form of the method according to the inventionapplies preferably when the internal diameter and the thickness of thefilm lie within the preferred ranges.

The length of the column is, in this alternative form, advantageously atleast 30 m. In a more particularly preferred way, it is greater than orequal to approximately 40 m. The length of the column is advantageouslyat most 100 m. In a more particularly preferred way, it is less than orequal to approximately 60 m.

In this alternative form, the temperature gradient as defined above isgenerally at least 10° C./min. It is preferably at least 20° C./min. Ina more particularly preferred way, the gradient is greater than or equalto approximately 40° C./min. The temperature gradient in thisalternative form is generally at most 50° C./min.

The initial temperature in this alternative form is generally at most−10° C. It is preferably less than or equal to −20° C. The initialtemperature in this alternative form is generally at least −50° C.

This alternative form of the method according to the invention makes itpossible, surprisingly, to further accelerate the analytical operationwhile retaining the other advantages of the method according to theinvention, in particular with respect to the simultaneous detection anddetermination of the organic impurities.

Premanufactured gas chromatography columns which make it possible toimplement the method according to the invention are availablecommercially, for example Rtx®-624 from Restec and DB®-624 from J & W.

Detection by mass spectrometry is preferably carried out using theselected ion monitoring (SIM) technique.

According to another preferred alternative form, detection by massspectrometry is carried out using the time-of-flight (TOF) technique.Mass spectrometers for detection by using the time-of-flight technique,which are preferred in the method according to the invention, make itpossible to record a high number of mass spectra per second, namelyapproximately 1 to 500, preferably 100 to 500, spectra per second.Spectrometers which can be used for the implementation of the methodaccording to the invention are, for example, those sold by LecoCorporation under the name Pegasus® II and those sold by Thermoquestunder the name Tempus™.

The hydrofluoroalkanes for which the content of organic impurities canbe analysed by the method according to the invention are the same asthose obtained according to the process according to the invention. Themethod according to the invention applies, preferably, to the analysisof 1,1,1,2-tetrafluoroethane or of 1,1,1,2,3,3,3-heptafluoropropane. Itapplies in particular to the analysis of 1,1,1,2-tetrafluoroethane.

The method according to the invention is particularly efficient asdetermination of the content of all the organic impurities can beobtained by a single analytical operation. That being the case, onlythis operation has to be validated, that is to say standardized andconfirmed. Consequently, the calibration possibly needed between theanalysis of various samples is simplified.

The method according to the invention makes it possible to achieve avery short duration necessary for the analysis, which can typically becarried out in less than two hours, often in less than one hour. Acomplete analysis of the impurities can be arrived at in a time ofapproximately 10 minutes. This efficiency makes it possible inparticular to improve the performance of industrial manufacturingprocesses requiring control of the quality of a hydrofluoroalkane. Thisis because it is possible to meet, with greater flexibility and speed,urgent orders for hydrofluoroalkane and reduce the hydrofluoroalkanestorage times.

The invention consequently also relates to a process for the manufactureof a hydrofluoroalkane comprising the use of the analytical methodaccording to the invention for controlling the quality of thehydrofluoroalkane.

In an alternative form, the hydrofluoroalkane is a purifiedhydrofluoroalkane. In this alternative form, the process for themanufacture of a hydrofluoroalkane often comprises a purification stage.This process preferably comprises

-   (a) the use of the method according to the invention for the    analysis of a crude hydrofluoroalkane;-   (b) a purification of the crude hydrofluoroalkane in order to obtain    a purified hydrofluoroalkane;-   (c) and a second use of the method according to the invention for    the analysis of the purified hydrofluoroalkane.

If appropriate, the purification can be carried out, for example,according to the production process according to the invention. Theprocess for manufacturing a hydrofluoroalkane according to the inventionpreferably applies to the hydrofluoroalkanes mentioned above.

The invention also relates to a process for the manufacture of apharmaceutical aerosol, comprising at least one hydrofluoroalkane ofpharmaceutical grade, comprising the use of the analytical methodaccording to the invention for controlling the quality of thehydrofluoroalkane of pharmaceutical grade.

The process for the manufacture of a pharmaceutical aerosol according tothe invention is particularly suitable for the manufacture of apharmaceutical aerosol for inhalation comprising at least onehydrofluoroalkane liquefied under pressure and a medicament. Themedicament is preferably present in the form of a powder in thesuspended state. The hydrofluoroalkane is present as propellent gas.

The process for the manufacture of a pharmaceutical aerosol isparticularly advantageous as the analytical method makes it possible tocarry out, in a particularly efficient way, the strict quality controllaid down for pharmaceutical applications.

The invention also relates to the use of the hydrofluoroalkane accordingto the invention as propellent gas in pharmaceutical aerosols.

The invention also relates to the use of the hydrofluoroalkane accordingto the invention in the electronics industry.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents a diagram of a plant which can be used forimplementing the preferred alternative form of the production processaccording to the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 represents a diagram of a plant which can be used forimplementing the preferred alternative form of the production processaccording to the invention. The numbers refer to FIG. 1. Thehydrofluoroalkane comprising organic impurities is introduced via route(1) into a first distillation column (2). At the top (3) of this column(2), a fraction is obtained comprising light impurities (lower butsimilar boiling point) and those which form a minimum-boiling azeotropeat this pressure. At the bottom (4) of this column (2), a fraction isobtained comprising hydrofluoroalkane with a reduced content of otherimpurities, which fraction is introduced via route (5) into the seconddistillation column (6) operating at a higher pressure than the column(2). At the bottom (7) of the second column (6), a fraction is recoveredwhich is enriched in heavy impurities which exhibit a higher boilingpoint with respect to that of the hydrofluoroalkane. At the top (8) ofthe second column (6), hydrofluoroalkane is obtained which is purifiedfrom organic impurities.

The examples given below are intended to illustrate, without impliedlimitation, the process, the analytical method and a hydrofluoroalkaneaccording to the invention.

EXAMPLE 1 In Accordance with the Invention

An impure 1,1,1,2-tetrafluoroethane fraction comprising 57.2 molar ppmof saturated organic impurities and 10.6 molar ppm of unsaturatedorganic impurities was employed. This fraction was introduced at thelevel of the 7th theoretical plate into a first distillation columncomprising 20 theoretical plates. The pressure in the first column was6.75 bar abs. A reflux ratio of 250 was provided. A fraction waswithdrawn at the top corresponding to 10% of the feed and comprising51.4 molar ppm of saturated organic impurities and 3.9 molar ppm ofunsaturated organic impurities. A fraction was recovered at the bottomcomposed of 1,1,1,2-tetrafluoroethane and purified from “light”impurities comprising 41.5 molar ppm of saturated organic impurities and34.9 molar ppm of unsaturated organic impurities, which fraction wasintroduced at the level of the 13th plate into a second distillationcolumn comprising 20 theoretical plates. The pressure in this seconddistillation column was 19.3 bar absolute. A reflux ratio of 14.8 wasprovided. At the column bottom, 10% of the feed of the first column,comprising 320 molar ppm of saturated organic impurities and 9.8 molarppm of unsaturated organic impurities was withdrawn. A fraction waswithdrawn at the top of this column composed of1,1,1,2-tetrafluoroethane purified from heavy impurities comprising 10.7molar ppm of saturated organic impurities and 1.3 molar ppm ofunsaturated organic impurities.

EXAMPLE 2 Not in Accordance with the Invention

An impure 1,1,1,2-tetrafluoroethane fraction comprising 2 750 molar ppmof saturated organic impurities and 75 molar ppm of unsaturated organicimpurities was employed. This fraction was introduced at the level ofthe 14th theoretical plate into a first distillation column comprising20 theoretical plates. The pressure in the first column was 13 bar abs.A reflux ratio of 50 was provided. A fraction was withdrawn at the topcorresponding to 10% of the feed and comprising 1 950 molar ppm ofsaturated organic impurities and 150 molar ppm of unsaturated organicimpurities. A fraction was recovered at the bottom composed of1,1,1,2-tetrafluoroethane purified from “light” impurities comprising 2950 molar ppm of saturated organic impurities and 40 ppm of unsaturatedorganic impurities, which fraction was introduced at the level of the14th plate into a second distillation column comprising 20 theoreticalplates. The pressure in this second distillation column was 12 barabsolute. A reflux ratio of 12.5 was provided. At the column bottom, 10%of the feed of the first column, comprising 15 500 molar ppm ofsaturated organic impurities and 50 molar ppm of unsaturated organicimpurities, was withdrawn. A fraction was withdrawn at the top of thiscolumn composed of 1,1,1,2-tetrafluoroethane purified from heavyimpurities comprising 275 molar ppm of saturated organic impurities and31 molar ppm of unsaturated organic impurities.

EXAMPLE 3 Not in Accordance with the Invention

An impure 1,1,1,2-tetrafluoroethane fraction, comprising 2 950 molar ppmof saturated organic impurities and 50 molar ppm of unsaturated organicimpurities, was employed. This factor was introduced at the level of the14th theoretical plate into a first distillation column comprising 20theoretical plates. The pressure in the first column was 7.5 bar abs. Areflux ratio of 50 was provided. A fraction was withdrawn at the topcorresponding to 10% of the feed and comprising 1 830 molar ppm ofsaturated organic impurities and 200 molar ppm of unsaturated organicimpurities. A fraction was recovered at the bottom composed of1,1,1,2-tetrafluoroethane purified from “light” impurities comprising 3200 molar ppm of saturated organic impurities and 32 ppm of unsaturatedorganic impurities, which fraction was introduced at the level of the14th plate into a second distillation column comprising 20 theoreticalplates. The pressure in this second distillation column was 6.5 barabsolute. A reflux ratio of 12.5 was provided. At the column bottom, 10%of the feed of the first, column, comprising 27 500 molar ppm ofsaturated organic impurities and 50 molar ppm of unsaturated organicimpurities, was withdrawn. At the top of this column, a fraction waswithdrawn composed of 1,1,1,2-tetrafluoroethane purified from heavyimpurities comprising 200 molar ppm of saturated organic impurities and28 molar ppm of unsaturated organic impurities.

EXAMPLE 4

An analysis of 1,1,1,2-tetrafluoroethane of pharmaceutical gradeobtained according to a production process in accordance with theinvention was carried out. To do this, gas chromatography was carriedout on an Rtx®-1 gas chromatography column sold by Restek Corp.comprising, as stationary phase, 100% of dimethylpolysiloxanecrosslinked by the Crossbond® process. The dimensions of the column were105 m×0.25 mm×1.0 micron. A temperature programme comprising 2 stageswas used, the first beginning at −50° C., and the temperature was raisedat a rate of 1° C./min to a temperature of 0° C. Subsequently, in asecond stage, the temperature was raised at a rate of 10° C./min to 250°C. Detection was carried out by mass spectrometry with the selected ionmonitoring (SIM) technique using an HP 5972 mass spectrometer sold byHewlett-Packard. Standardization was carried out by employing a gasstandard mixture composed of 10 ppm of each impurity to be analysed.

The contents of various impurities in the 1,1,1,2-tetrafluoroethaneaccording to the invention and in the crude 1,1,1,2-tetrafluoroethanewhich is employed in the process according to the invention are shown inthe table below. The detection limit of the analytical method accordingto the invention is also shown. This detection limit was validated byrandom calibration with respect to 5 concentrations of 1 to 10 ppm ofeach individual impurity. The values obtained were corrected accordingto the purity of each of the impurities present in the calibrationmixture.

The table also includes the values contained in the draft FDA standardmentioned above. All the values are expressed in molar ppm, apart fromthe “Assay” value, which is expressed as a percent. An empty box meansthat the impurity in question was not observed.

Detection limit of the method Draft Crude HFC- Organic according to FDAHFC- 134A impurity Formula the invention standard 134a Invention HFC-23CHF₃ 0.2 5 CFC-13 CClF₃ 0.3 5 < HFC-32 CH₂F₂ 0.2 5 HFC-125 CHF₂—CF₃ 0.35 50 HFC-143a CH₃—CF₃ 0.4 10 124 CFC-115 CClF₂—CF₃ 0.2 5 0.3 HFC-1123CHF═CF₂ 0.2 5 c/t-HFC- CF₃—CF═CF—CF₃ 0.7 5 1318my t/c-HFC- CF₃—CF═CF—CF₃0.3 5 < < 1318my (1) HFC-245cb CF₃—CF₂—CH₃ 0.2 5 0.3 HFC-1234yfCH₂═CF—CF₃ 0.3 5 1.3 HFC-134 CHF₂—CHF₂ 0.4 1 000 2 824 < HFC-152aCH₃—CHF₂ 0.2 300 1.3 HFC-217ba CF₃—CCIF—CF₃ 0.5 5* 2.4 0.5 HFC-161CH₃—CH₂F 0.2 30 HFC-1225ye CHF═CF—CF₃ 0.2 5 1.8 HFC-1243zf CH₂═CH—CF₃0.4 5 7.3 0.9 HFC-1132 CHF═CHF 0.4 5 < C₃H₂F₄ (2) 0.3 5* 11.8 HCFC-22CHClF₂ 0.2 50 0.2 HFC- CF₃—CH═CH—CF₃ 0.5 5 1336mzz CFC-12 CCl₂F₂ 0.2 1000.2 HCC-40 CH₃Cl 0.4 5 4.0 HCFC-124a CHF₂—CClF₂ 0.2 5 HCFC-124 CHClF—CF₃0.4 100 36 HCFC-1122 CHCl═CF₂ 0.3 5 28 0.3 HCFC-31 CH₂ClF 0.4 5 0.4CFC-114 CClF₂—CClF₂ 0.1 5 CFC-114a CCl₂F—CF₃ 0.1 25 19 HFC-152 CH₂F—CH₂F0.5 5 c/t-HCFC- CHF═CClF 0.3 5* 4.6 1122a (3) c/t-HCFC- CHF═CClF 0.3 5*< 1122a (3) HCFC-133a CH₂Cl—CF₃ 0.4 5 0.4 trans- CHCl═CHF 0.5 5* 10.30.2 HCFC-1131 cis-HCFC- CHCl═CHF 0.5 5* 1131 CFC-12B1 CClBrF₂ 0.2 5CFC-1112a CF₂═CCl₂ 0.3 5 HCFC-123 CHCl₂—CF₃ 0.4 5 CFC-11 CCl₃F 0.3 5HCFC-123a CHClF—CClF₂ 0.3 5 c/t-HCFC- CHCl═CClF 0.2 5 1121 HCC-30 CH₂Cl₂0.6 5* < HCFC-132b CClF₂—CH₂Cl 0.6 5 CFC-113 CClF₂—CCl₂F 0.4 5 HCC-1120CHCl═CCl₂ 0.8 5* < < Sum of 1 000 3 127.6 1.9 organic impurities Sum of5 65.1 1.4 olefins Assay 99.9% 100%   < below the detection limit Theimpurities for which the content is below the detection limit were nottaken into consideration in calculating the sums of impurities. (1)Estimated value (2) Value calculated by taking into consideration theresponse factor of HFC-1234yf (3) E/Z isomers, value calculated bytaking into consideration the response factor of HCFC-1122 *Compound notmentioned individually in the draft FDA standard.

It is apparent that the 1,1,2,2-tetrafluoroethane according to theinvention, obtained in accordance with the process according to theinvention, exhibits a content of organic impurities which is extremelylow and far below the values of the draft FDA standard. Furthermore, noindividual organic impurity has a content exceeding 1 molar ppm.

It is also apparent that the method according to the invention makes itpossible to detect and to identify, with an extremely high sensitivity,all the impurities included in the draft FDA standard.

1. A method for the analysis of the content of organic impurities in apharmaceutical grade 1,1,1,2 tetrafluoroethane which comprises the stepsof (a) subjecting the 1,1,1,2 tetrafluoroethane to a chromatographyoperation and (b) carrying out an operation in which the organicimpurities are detected by mass spectrometry and wherein the method iscapable of detecting the impurities at 0.8 molar ppm.
 2. The methodaccording to claim 1, in which the chromatography operation is a gaschromatography operation.
 3. The method according to claim 2, in whichthe initial temperature of the chromatography operation is adjusted atthe most to 40° C.
 4. The method according to claim 3, in which theinitial temperature of the chromatography operation is less than orequal to approximately −20° C.
 5. The method according to claim 1, inwhich detection is carried out using the selected ion monitoring (SIM)technique.
 6. The method according to claim 1, in which detection iscarried out using the time-of-flight (TOF) technique.
 7. The methodaccording to claim 1, wherein at least one of the organic impuritiesdetected is selected from group consisting of CHF₃, CClF₃, CH₂F₂,CHF₂—CF₃, CH₃—CF₃, CClF₂—CF₃, CHF═CF₂, CF₃—CF═CF—CF₃, CF₃═CF—CF₃,CF₃—CF₂—CH₃, CH₂═CF—CF₃, CHF₂—CHF₂, CH₃—CHF₂, CF₃—CClF—CF₃, CH₃—CH₂F,CHF═CF—CF₃, CH₂═CH—CF₃, CHF═CHF, CHClF₂, CF₃—CH═CH—CF₃, CCl₂F₂, CH₃Cl,CHF₂—CClF₂, CHClF—CF₃, CHCl═CF₂, CH₂ClF, CClF₂—CClF₂, CCl₂F—CF₃,CH₂F—CH₂F, CHF═CClF, CHF═CClF, CH₂Cl—CF₃, CHCl—CHF, CHCl═CHF, CClBrF₂,CF₂═CCl₂, CHCl₂—CF₃, CCl₃F, CHClF—CClF₂, CHCl═CClF, CH₂Cl₂, CClF₂—CH₂Cl,CClF₂—CCl₂F and CHCl═CCl₂.
 8. The method according to claim 1, whereinthe organic impurities detected are selected from group consisting ofCF₃—CClF—CF₃, CH₂═CH—CF₃, CHCl═CF₂ and CHCl═CHF.
 9. The method accordingto claim 1, wherein the organic impurities detected are CF₃—CClF—CF₃,and CH₂═CH—CF₃.
 10. A method for the analysis of the content of organicimpurities in a hydrofluoroalkane which comprises the steps of (a)subjecting the hydrofluoroalkane to a chromatography operation and (b)carrying out an operation in which the organic impurities are detectedby mass spectrometry and wherein said hydrofluoroalkane is selected fromthe group consisting of 1,1,1,2,3,3,3-heptafluoropropane,1,1,1,3,3-pentafluoropropane, 1,1,1,3,3-pentafluorobutane and1,1,1,2-tetrafluoroethane and the quantitative detection of impuritieswhich exhibit the same retention time in the chromatography operation asthe hydrofluoroalkane.
 11. The method according to claim 10, in whichthe chromatography operation is a gas chromatography operation.
 12. Themethod according to claim 11, in which the initial temperature of thechromatography operation is adjusted at the most to 40° C.
 13. Themethod according to claim 12, in which the initial temperature of thechromatography operation is less than or equal to approximately −20° C.14. The method according to claim 10, in which detection is carried outusing the selected ion monitoring (SIM) technique.
 15. The methodaccording to claim 10, in which detection is carried out using thetime-of-flight (TOF) technique.
 16. The method according to claim 15, inwhich the hydrofluoroalkane is 1,1,1,2-tetrafluoroethane.
 17. The methodaccording to claim 10, wherein at least one of the organic impuritiesdetected is selected from group consisting of CHF₃, CClF₃, CH₂F₂,CHF₂—CF₃, CH₃—CF₃, CClF₂—CF₃, CHF═CF₂, CF₃—CF═CF—CF₃, CF₃═CF—CF₃,CF₃—CF₂—CH₃, CH₂═CF—CF₃, CHF₂—CHF₂, CH₃—CHF₂, CF₃—CClF—CF₃, CH₃—CH₂F,CHF═CF—CF₃, CH₂═CH—CF₃, CHF═CHF, CHClF₂, CF₃—CH═CH—CF₃, CCl₂F₂, CH₃Cl,CHF₂—CClF₂, CHClF—CF₃, CHCl═CF₂, CH₂ClF, CClF₂—CClF₂, CCl₂F—CF₃,CH₂F—CH₂F, CHF═CClF, CHF═CClF, CH₂Cl—CF₃, CHCl—CHF, CHCl═CHF, CClBrF₂,CF₂═CCl₂, CHCl₂—CF₃, CCl₃F, CHClF—CClF₂, CHCl═CClF, CH₂Cl₂, CClF₂—CH₂Cl,CClF₂—CCl₂F and CHCl═CCl₂.
 18. The method according to claim 10, whereinthe organic impurities detected are selected from group consisting ofCF₃—CClF—CF₃, CH₂═CH—CF₃, CHCl═CF₂ and CHCl═CHF.
 19. The methodaccording to claim 10, wherein the organic impurities detected areCF₃—CClF—CF₃ and CH₂═CH—CF₃.